Activity Dependent Regulation of Gene Expression in AgRP Neurons is Driven by HFD to Promote DIO

项目总结/摘要 肥胖及其相关合并症（糖尿病、心脏病、高血压等）目前正在折磨 美国有超过1.14亿人，缺乏有效的治疗方案，这反映在 预计到2030年将增加到近1.5亿人。过量的热量摄入是肥胖的主要原因， 然而，驱动过量食物摄入的神经机制（可能是 肥胖症）仍然未被识别。先前对啮齿动物的研究一致表明，高饱和脂肪和 糖增加负责维持能量稳态神经元回路的兴奋性。这种增加的 兴奋性与增加的食物摄入、体重和瘦素不敏感性一致。然而，时间进程 对于这些影响和潜在的突触变化的重要性尚不清楚。这些变化可能会推动 发展和维持饮食引起的肥胖，以及减肥困难或体重增加后， 减肥. 弓状核内的Agouti-related peptide（AgRP）/neuropeptide-Y（NPY）神经元 下丘脑是负责食物摄取的主要神经元群。AgRP神经活动迅速， 可靠地启动食物寻求行为，这通常通过禁食或热量限制来增强， 开始进食后消退。此外，AgRP神经元活性在以下持续升高： 高脂饮食（HFD）喂养。我们的初步数据表明，短期和长期HFD对 突触可塑性和信号整合到AgRP/NPY神经元。具体而言，短期（2天）HFD增加 AgRP神经元的兴奋性信号传导。然而，长期（8周）HFD导致持续的AgRP神经 活性，尽管抑制性信号传导增加。由于这些影响的机制仍然很差， 理解，我的目标是利用先前映射的兴奋性和抑制性输入来探测HFD诱导的 突触可塑性和AgRP神经元活性。我还将使用AgRP特异性RNA测序来鉴定 与短期和长期HFD喂养相关的转录变化。通过将电生理学与 - 组学方法，我将确定先验基因，并优先考虑新的候选基因进行验证研究， 短期和长期HFD喂养的小鼠。这些将集中在已报道的兴奋性或抑制性输入的改变 以及摄食行为和体重增加的表型变化。 饮食诱导的AgRP/NPY神经元群体内神经机制的改变至关重要 来理解体内平衡失调。确定驱动HFD诱导的 肥胖症是未来开发对抗饮食诱导的肥胖症的新治疗策略的关键。 总的来说，这项研究计划提出的实验，预期发现以前未描述的 急性或慢性消耗致肥胖饮食后的食欲行为刺激剂。

PROJECT SUMMARY/ABSTRACT Obesity and its related comorbidities (diabetes, heart disease, hypertension, etc.) currently afflicts more than 114 million people in the United States and the absence of effective treatment options is reflected by the projected rise to nearly 150 million people by 2030. Excess caloric intake is the primary cause of obesity, however, the neural mechanisms driving superfluous food intake (and likely underlie the pathogenesis of obesity) remain unidentified. Previous studies in rodents consistently show that diets high in saturated fat and sugar increase excitability of neuronal circuits responsible for maintaining energy homeostasis. This increased excitability coincides with increased food intake, body-weight, and leptin insensitivity. However, the time course for these effects and the importance of underlying synaptic changes are unclear. These changes likely drive development and maintenance of diet-induced obesity, as well as difficulty losing weight or weight gain after weight loss. Agouti-related peptide (AgRP)/ neuropeptide-Y (NPY) neurons in the arcuate nucleus of the hypothalamus are the primary neuronal population responsible for food intake. AgRP neural activity rapidly and reliably initiates food seeking behavior, which is typically enhanced by fasting or caloric restriction and subsides upon initiation of meal consumption. Further, AgRP neuronal activity is consistently elevated following high fat diet (HFD) feeding. Our preliminary data suggest divergent effects of short- and long-term HFD on synaptic plasticity and signal integration to AgRP/NPY neurons. Specifically, short-term (2 day) HFD increases excitatory signaling to AgRP neurons. However, long-term (8 weeks) HFD results in sustained AgRP neural activity despite increased inhibitory signaling. Since the mechanisms underlying these effects remain poorly understood, my objective is to utilize previously mapped excitatory and inhibitory inputs to probe HFD-induced synaptic plasticity and AgRP neuronal activity. I will also use AgRP-specific RNA sequencing to identify transcriptional changes related to both short- and long-term HFD feeding. By pairing electrophysiology with an –omics approach, I will identify a priori genes and prioritize novel candidate genes for validation studies in both short- and long-term HFD fed mice. These will focus on the reported alterations to excitatory or inhibitory inputs and phenotypic changes in feeding behavior and weight gain. Diet-induced alterations to neural mechanisms within the AgRP/NPY neuronal population, are crucial for understanding homeostatic dysregulation. Identification of the underlying mechanisms driving HFD-induced obesity are critical for future development of novel therapeutic strategies to combat diet-induced obesity. Overall, this research program proposes experiments that anticipate the discovery of previously undescribed stimulators of appetitive behavior following acute or chronic consumption of obesogenic diet.